7qjk
Crystal structure of PDE6D in complex with Compound-2
Structural highlights
FunctionPDE6D_HUMAN Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity). Publication Abstract from PubMedRAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed. Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.,Yelland T, Garcia E, Parry C, Kowalczyk D, Wojnowska M, Gohlke A, Zalar M, Cameron K, Goodwin G, Yu Q, Zhu PC, ElMaghloob Y, Pugliese A, Archibald L, Jamieson A, Chen YX, McArthur D, Bower J, Ismail S J Med Chem. 2022 Feb 10;65(3):1898-1914. doi: 10.1021/acs.jmedchem.1c01265. Epub , 2022 Feb 1. PMID:35104933[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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